#2020BSQ-NOV/Q10
#2020BSQ-NOV/Q20

Adverse drug reactions

#2020BSQ-NOV/Q18

Adverse drug reaction: A noxious and unintended response to a drug that occurs during usual clinical use.

Adverse drug event: any unexpected or inappropirate occurence that occurs during drug administration. Does not necessarily have a causal relationship to the drug administration.

Intentional overdose and prescribing errors are not adverse drug reactions.

What is meant by idiosyncratic:

Drug idiosyncrasy—A genetically determined, qualitatively abnormal reaction to a drug related to a metabolic or enzyme deficiency
(i.e when some patient factor interacts with drug pharmacology to create the adverse reaction).

[!TIP] mnemonic: 'flozins' are SGLT-2 inhibitors
Glucose 'flows in' the PCT

| Sitagliptin Linigliptin | DPP-4 inhibitors (gliptins) | Inhibit GLP-1 breakdown (restore physiologic GLP levels) → promotion of insulin secretion GLP1 receptors are also found in the cardiovascular system | Good S/E profile. | Used as second line drug, in early DM when insulin secretion is still preserved. Combined with metformin / sulfonylurea | Modest effect but used because of low S/E profile. |
Basis: GLP-1 and GIP are incretin hormones.
Reduce apetite -> weight loss
No benefit from combining with DPP4 inhibitors.

Effective renal plasma flow can be calculated using the Fick principle with para-amino hippuric acid. This is a substance that is filtered and secreted by the kidney (but not reabsorbed) meaning that almost all of it is removed in a pass through the kidney. (extraction ratio is around 90%).

#2020BSQ-NOV/Q02

It is the most common cause of lactase deficiency, also known as lactase non-persistence. There is a gradual decline in lactase enzyme activity with increasing age. Enzyme activity begins to decline in infancy, and symptoms manifest in adolescence or early adulthood.

Secondary Lactase Deficiency
Due to several infectious, inflammatory, or other diseases, injury to intestinal mucosa can cause secondary lactase deficiency. Common causes include:

• Gastroenteritis
• Celiac disease
• Crohn disease
• Ulcerative colitis
• Chemotherapy
• Antibiotics

Types of cellular receptors

There are 4 types of receptors:

1. Ligand gated ion channels: timescale is milliseconds
   1. role: fast neutrotransmitters :
2. G-protein coupled receptors ("7 transmembrane receptors): timescale is seconds.
   1. Largest family of receptors; "metabotropic";
   2. hormone receptors and slow transmitters;
3. Kinase linked and kinase related receptors: timescale - hours
   1. heterogenous group; triggered by protein mediators.
   2. They have a single transmembrane domain. Intracellular transduction is mediated by a protein kinase or guanyl cylcase.
      1. Guanyl cyclase is an enzyme which catalyzes the synthesis of cyclic guanosine 3′,5′-monophosphate (cGMP)
4. Nuclear receptors: Timescale - Hours
   1. They regulate gene transcriptions.
      
      

G protein coupled receptors (GPCR)

[!TIP]
This Source is very good and agrees with Rang and Dale but is much shorter and is the source for all the images.

Incredibly short overview:

• G proteins are transmembrane proteins with 7 transmembrane domains.
• Examples of GPCR based signalling pathways: catecholamines, histamine, serotonin, opioids, cannabinoid, amines, peptides, prostanoids.
• The third transmembrane domain can bind to 'G proteins' on the intracellular side.
• The G proteins are proteins floating around on the underside of the cell membrane. They have alpha, beta and gamma subunits. There are 4 distinct alpha subunit classes but the beta and gamma are common to all types of G proteins.
  • The alpha subunits are specific to particular GPC-receptors and to particular second messenger molecules.
• When a GPRC is stimulated by its ligand, it gains the ability to activate G proteins.
• When a G protein is activated, it's alpha subunit gains GTP-ase activity.
• This activated alpha subunit breaks away from the beta-gamma remainder and moves off to activate one of several possible second messenger molecules.
• Once the second messenger is stimulated, the alpha subunit loses it's GTP-ase activity and rejoins the beta-gamma remainder so that it can be reactivated by the GPCR. (However, the beta-gamma subunit is not just a passive chaperone; it is also involved in signal transduction)
• The second messengers:
  1. Adenylyl cyclase - an enzyme which synthesizes cAMP from ATP, when activated.
  2. Phospholipase C and inositol:
  3. Rho A / Rho kinase - involved in cell growth pathways and smooth muscle contraction
  4. mitogen-activated protein kinase - MAP kinase. (controls things like cell division)
• Note that stimulation of Galpha-s associated receptors activates adenylyl cyclase but stimulation of G-alpha-i associated receptors inactivates adenylyl cyclase.
  

cAMP (cyclic AMP)

• cAMP - generated by activation of adenylyl cyclase - activates protein kinases.
• One important protein kinase is protein kinase A (PKA)
• Protein kinases like PKA activate many enzymes (and ion channels) which regulate cellular metabolism or myosin light chain kinase which is required for smooth muscle contraction. (Phosphorylation of myosin light chain kinase inactivates it causing smooth muscle relaxation).
• cAMP is degraded by phosphodiesterase.
• There are many subtypes of Phosphodiesterases. Some specifically degrade cAMP while other specifically degrade cGMP.
  • Milrinone - PDE3 inhibitor
  • Sildenafil - PDE5 inhibitor
  • Theophylline - weak inhibitor of most isoforms of phosphdiesterase.

Phospholipase C / inositol triphosphate / diacylglycerol

• The second most important GPCR coupled second messenger.
• Activated by Galpha-q containing G proteins.
• Activation catalyzes the formation of intracellular messengers IP3 and DAG from membrane phospholipids.
• IP3 increases cytosolic Ca by release it from intracellular compartments.
• The calcium acivates enzymes and effects many changes.
• DAG activates protein kinase C which also controls many functions.

[!TIP]
The nitocinic receptors (which is a ligand gated ion channel) is found at the neuromusclar junction.

Tyrosine kinases

Adenylyl cyclase and cAMP system

One of the targets of G proteins.

Alveolar arterial oxygen gradient increases in CO poisoning.

Antipseudomonal carbapenems – imipenem, meropenem and doripenem – have excellent activity against most strains of many bacterial species and are regarded as safe and generally well-tolerated. Of note, these carbapenems are resistant to ESBLs, and so are of value in treating infections caused by ESBL-producing strains of Enterobacteriaceae
Source

#2020BSQ-NOV/Q19

• It has metallo-beta lactamases which inactivate all beta lactams including carbapenems.
  • Two agents from different classes should be used when the risk for antibiotic resistance is high
  • carbapenems except ertapenem.

Pharmacokinetics overview

[!INFO] Pharmacokinetics Vs. Pharmacodynamics
Dynamics = 'power'
Pharmacodynamics = effect drugs have on the body.
Pharmacokinetics = effect body has on drug concentrations.

Bioavailability

#2020BSQ-NOV/Q17

• The fraction of orally administered drug dose drug that reaches the circulation intact (i.e after the effects of first pass metabolism)
• Bioavailability of an IV drug is 1 by definition.
• In other words, bioavailablity is reduced both by decreased absorption and by breakdown by hepatic and intestinal enzymes. [[General Pharmacology#First pass metabolism]]

$$
Bioavailability=\frac{AUC_{oral}}{AUC_{IV}}
$$
where AUC = area under the curve for drug concentration Vs. time graph.

• Bioequivalence indicates that the drug products, when given to the same patient in the same dosage regimen, result in equivalent concentrations of drug in plasma and tissues.
• Therapeutic equivalence indicates that drug products, when given to the same patient in the same dosage regimen, have the same therapeutic and adverse effects.
• Bioequivalent drugs are generally expected to be therapeutically equivalent.

Effect of liver failure on pharmacokinetics

Mathematics of hepatic pharmacokinetics

Source

[!INFO]
Extraction ratio : Hepatic extraction ratio ... is the fraction of the drug entering the liver in the blood which is irreversibly removed (extracted) during one pass of the blood through the liver.
$$
\large Extraction\space Ratio = \frac{C_{arterial} - C{venous}}{C_{arterial}}
$$
Protein binding affects hepatic extraction ratio because hepatocytes have access only to the unbound form of the drug.
Therefore, the equation above is equivalently represented as
$$
\large E_H = \frac{fu\times Cl_{int}}{Q_{H}+fu\times Cl_{int}}
$$

• (EH = hepatic extraction ratio)
• (Cl = intrinsic clearance)
  • Intrinsic clearance is the intrinsic ability of the liver to remove (metabolise) the drug in absence of restrictions imposed on drug delivery to the liver cell by blood flow or protein binding.
  • It basically expresses how powerful the liver enzymes are at removing a drug.
• Fu - Fraction of unbound drug in the plasma
• QH - hepatic blood flow
  Finally we have the following equation for hepatic clearance: (ClH)
  $$
  \large Cl_{H} = Q_{H} \times \frac{fu\times Cl_{int}}{Q_{H}+fu\times Cl_{int}}
  $$
  So, we can see that hepatic clearance is affected by

1. Hepatic blood flow
2. Unbound fraction of the drug
3. Intrinsic ability of the liver to metabolize the drug

[!INFO] The upshot
Drugs with low intrinsic clearance will have "intrinsic limited" clearance
Drugs with high intrinsic clearance will have "flow limited" clearance.

Effects in liver failure

In liver failure,

• There is increased body water -> volume of distribution is increased, lowering drug concentration.
• Hypoalbuminaemia / hypoproteinaemia -> lower protein -> higher concentration of highly protein bound drugs -> eg Aspirin, warfarin, phenytoin, benzodiazepines.
• Bilirubin can displace drugs from bound proteins -> increased Fu above. (?mild effect of increasing clearance)
• Intrinsic clearance will be reduced -> hepatic clearance is reduced -> higher drug concentrations.
• Hepatic blood flow is reduced due to
  • portosystemic shunting. [[2020-NOV-BasicSciences#Mechanism of porto-systemic shunting]] -> hepatic clearance is reduced.
  • Inotropes causing splanchnic vasoconstriction -> reduced hepatic blood flow.
  • Most drugs have low extraction ratios and clearance is dependent on intrinsic clearance capacity of the liver.

The A-a gradient tends to increases with age.
(A-a gradient = 2.5 + FiO2 x age in years<-- Source )

Of the 5 causes of hypoxaemia, elevated A-a gradient excludes hypoventilation and low FiO2 as the causes.
The 5 causes must be written down somewhere else but just in case:

1. V/Q mismatch, R->L shunt, Diffusion impairement, Low FiO2, hypoventilation)

Increased in

• defects of alveolar / capillary unit. (diffusion impairment - uncommon)
• V/Q mismatch (the most common cause of hypoxaemia)
• Right to left shunt - intracardiac, or intrapulmonary (i.e [[2021-Basic Sciences#Arteriovenous malformation|AV malformations]]) ( #2021BSQ-NOV/Q05)
• Increased O2 extraction

Normal in

• Hypoventilation (i.e poor oxygen delivery) (because PAO2 and PaO2 are both reduced)
• Fi02 < 21%

Source